Project Summary The basal ganglia are a group of subcortical nuclei, which?through their connections to the cortex and thalamus?are fundamental to voluntary movement and behavioral regulation. As a component of this network, the subthalamic nucleus (STN) plays a key role in the suppression of unwanted movements and impulses. Changes in the rate and/or pattern of STN activity are essential features of several neurological diseases, including Parkinson?s disease (PD), Huntington?s disease, hemiballism, and obsessive-compulsive disorder. Indeed, some of the most successful therapies for these diseases rely on deep brain stimulation of the STN. A better understanding of the influences governing STN activity is therefore paramount to dissecting the underlying pathophysiology and potentially enhancing treatments for these disorders. Toward that end, this project aims to evaluate the role of dopamine (DA) in directly modulating STN activity, both in health and in a mouse model of PD. As the second most common neurodegenerative disease, PD represents an enormous public health burden. It is generally assumed that degeneration of the nigro-striatal pathway is responsible for the motor symptoms of PD. However, substantia nigra (SN) DA neurons that innervate the STN are also susceptible to degeneration in PD, implying that loss of direct dopaminergic modulation may play a role in pathological STN activity. Importantly, STN hyperactivity and excessive cortical patterning are strong predictors of motor symptom severity in PD. Using a combination of pharmacology, ex vivo and in vivo electrophysiology, optogenetics, fast-scan cyclic voltammetry, chemogenetics, and behavioral analyses, the proposed experiments will address 2 specific aims: 1) to examine the physiological and behavioral impacts of nigro- subthalamic transmission, and 2) to determine whether local replacement of DA reverses pathological STN activity and motor dysfunction in experimental PD. The results of these experiments will elucidate the role of SN-STN signaling in normal STN function, will determine how loss of direct dopaminergic modulation of the STN contributes to PD pathology, and may also provide insight into extrastriatal mechanisms of DA- replacement therapy in PD.